Tropical Medicine and

Infectious Disease

Review
Current Status of the Sm14/GLA-SE Schistosomiasis
Vaccine: Overcoming Barriers and Paradigms towards
the First Anti-Parasitic Human(itarian) Vaccine
Miriam Tendler *, Marília S. Almeida, Monica M. Vilar, Patrícia M. Pinto and
Gabriel Limaverde-Sousa
FIOCRUZ—Instituto Oswaldo Cruz, Laboratório de Esquistossomose Experimental, Av. Brasil, 4365,
Manguinhos, Rio de Janeiro 21045-900, Brazil; sirianni@ioc.fiocruz.br (M.S.A.);
mvilar@ioc.fiocruz.br (M.M.V.); pmpinto@ioc.fiocruz.br (P.M.P.);
gabriel.sousa@ioc.fiocruz.br (G.L.-S.)
* Correspondence: tendlermiriam@gmail.com; Tel.: +55-21-2562-1320




Received: 15 October 2018; Accepted: 12 November 2018; Published: 21 November 2018


Abstract: Schistosomiasis, a disease historically associated with poverty, lack of sanitation and social
inequality, is a chronic, debilitating parasitic infection, affecting hundreds of millions of people in
endemic countries. Although chemotherapy is capable of reducing morbidity in humans, rapid
re-infection demonstrates that the impact of drug treatment on transmission control or disease
elimination is marginal. In addition, despite more than two decades of well-executed control
activities based on large-scale chemotherapy, the disease is expanding in many areas including Brazil.
The development of the Sm14/GLA-SE schistosomiasis vaccine is an emblematic, open knowledge
innovation that has successfully completed phase I and phase IIa clinical trials, with Phase II/III
trials underway in the African continent, to be followed by further trials in Brazil. The discovery
and experimental phases of the development of this vaccine gathered a robust collection of data
that strongly supports the ongoing clinical phase. This paper reviews the development of the
Sm14 vaccine, formulated with glucopyranosyl lipid A (GLA-SE), from the initial experimental
developments to clinical trials including the current status of phase II studies.

Keywords: schistosomiasis; vaccine; Sm14; FABP

1. Introduction
Schistosomiasis is the second-most socioeconomically devastating parasitic disease after malaria.
The disease is both chronic and debilitating with an estimated 200 million people infected, most of
whom (85%) live in Africa. Of those infected, 120 million are symptomatic and 20 million present
severe disease symptoms [1]. These estimates may err on the low side since meta-analysis has found
the number of people at risk to be closer to 800 million [2]. Globally, the impact of schistosomiasis
remains high and the estimated number of disability-adjusted life years (DALYs) has increased
with the inclusion of previously under-recognized morbidities not previously included in the DALY
index (for example, stunted growth and anemia associated with retarded intellectual development)
in infants, toddlers and school age children, whose physical health and intellectual capacity are
fundamental to nation development and sustainability [3,4]. In addition, high-definition circulating
antigen tests, such as the POC-CCA assay, indicate that the current number of infections may be at
least 10 times higher than that shown by egg detection [5]. In Brazil, the largest endemic country
for schistosomiasis, 6 million individuals are estimated to be infected and 25 million are at risk of
contracting the disease [6,7].

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Trop. Med. Infect. Dis. 2018, 3, 121 2 of 10

Mass chemotherapy has been the strategy of choice for the control schistosomiasis with the
support of international health funding agencies. Estimates show that at least 206.5 million people
were treated in 2016 [8]. However, the strategy of large-scale chemotherapeutic treatment, also
equivocally called ‘prophylactic treatment’, over a period of 30 years has failed to control schistosome
transmission. Approximately 300 million US dollars are being spent annually on treatments applied to
the same populations year after year with no prospect of preventing reinfection or the need for repeat
treatments [9]. ‘Deworming’ initiatives, originally applied to animal species only, were proposed as a
tool for schistosomiasis control programs focused on school children in endemic countries [10,11].
In the veterinary field, under One Health policies for the control of helminth infections such as
Fasciola hepatica, the major parasitic infection of livestock worldwide, there is a strong demand for the
replacement of anti-helminthic drugs with vaccines. This would significantly reduce the amount of
chemical residues in meat, milk and added-value products. Indeed, vaccines are considered to be the
most environmentally- and human health-friendly method of control of fascioliasis in livestock [12].
The potential introduction of vaccines into schistosomiasis control programs brings hope to the
poor living in endemic areas. The Brazilian Sm14 vaccine project was launched in the 1990s and strongly
pushed in the context of a formal WHO program aimed at the development of an anti-schistosomiasis
vaccine. The main outcome of this initiative was the selection of six priority antigen candidates of
which only Sm14, continues to be developed (Table 1, adapted from [13]).
With strategic support from WHO, the Sm14 vaccine, which is based on a recombinant protein, is
moving forward in an endemic country towards final development. It is being developed utilizing
sophisticated and modern technological platforms and professionally conducted within a network of
outstanding companies and collaborators. It is the result of long-term scientific developments carried
under the coordination of FIOCRUZ, a public institution linked to the Brazilian Ministry of Health and
is protected by strong patents, owned by FIOCRUZ, in all countries of interest worldwide.
Recently, the Consultative Expert Working Group on Research and Development: Financing
and Coordination (CEWG/WHO) selected the Sm14 vaccine as one of six demonstration projects,
globally, following an extensive review process. It was recognized as being fully in accordance with
the principles of CEWG, such as clear mechanisms of de-linkage of costs from investments in research
and development (R&D) from costs of final product, accessibility, affordability, viability and open
knowledge innovation. The CEWG recognized that the Sm14 vaccine may become a key tool for the
implementation of effective infection reduction and transmission control programs for schistosomiasis
that would not rely only on chemotherapy [14].
Over recent years it has been possible to complete important milestones in the development of
the vaccine including scaling up production process from laboratory bench to a clinical trial scale
as well as the successful conclusion of two phase I human trials in healthy adults (male and female)
living in a Brazilian non-endemic area (2011–2014) [15] together with a first phase II trial in 30 male
adults living in highly endemic area for both Schistosoma mansoni and S. haematobium at the Senegal
River Basin (2015–2017). In the latter, safety was extensively confirmed and strong and long-lasting
immunogenicity was also demonstrated (manuscript in preparation). Master cell bank generation has
recently been completed and production in good manufacturing practices (GMP) of a second Sm14 lot
is currently ongoing, under the coordination of the Infectious Disease Research Institute (IDRI, Seattle,
US). This article is an overview of the development of the Sm14 schistosomiasis vaccine development
from antigen discovery to the current human studies (Figure 1). The need to overcome barriers for the
establishment of a truly humanitarian vaccine—addressing the needs of the developing world—will
be discussed.
Trop. Med. Infect. Dis. 2018, 3, 121 3 of 10

Table 1. Schistosomiasis priority antigens selected by the WHO for independent testing (adapted from [13]).

Antigen Size (kDa) Stage Expressed Description Protection (%) Place of Development
Glutathione S-transferase
28 Adult/somula/egg Enzyme 30–60 Institut Pasteur, Lille, France
(P28/GST)
Case Western Reserve University/National
Paramyosin (Sm97) 97 Adult/somula Muscle protein 30
Institute of Health/Cornell University, USA
Johns Hopkins School of Medicine,
IrV-5 62 Adult/somula/egg Muscle protein 50–70
Baltimore, USA
Triose phosphate isomerase
28 Adult/somula/egg Enzyme 30–60 Harvard School of Public Health, Boston, USA
(TPI)
Johns Hopkins School of Medicine/Harvard
Sm23 23 Adult/somula/egg Integrated membrane protein 40–50
School of Public Health, USA
Sm14 14 Adult/somula Fatty acid-binding protein 65 Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
Trop. Med.
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Figure 1. Timeline: Sm14/GLA-SE anti-schistosomiasis vaccine - from discovery phase to final product. MAPA: Brazilian Ministry of Agriculture.
Figure 1. Timeline: Sm14/GLA-SE anti-schistosomiasis vaccine - from discovery phase to final product. MAPA: Brazilian Ministry of Agriculture.
Trop. Med. Infect. Dis. 2018, 3, 121 5 of 10

2. Innovative Strategies Adopted for Antigen Discovery and Early Development Phases
Biotechnological advances in various areas of vaccine research have contributed to the development
of safer and more effective formulations. Efforts to develop anti-helminth vaccines have been ongoing
for many years and are continuing to progress in the identification of candidate antigens. These efforts
have recently been boosted by the generation of a number of helminth genome sequences [16]. The
development of a vaccine against schistosomiasis would represent an important step in the context of
research and development in public health for poor populations infected and exposed to schistosomes.
There have been initiatives to develop a vaccine against schistosomiasis from research groups in different
countries. The Brazilian Sm14-based anti-schistosomiasis vaccine is the only one of these initiatives that
is currently undergoing clinical trials [17].
In contrast to the current ‘OMICS’ strategies, in which high-throughput screening of potential
target antigens are processed in parallel by automated ‘discovery protocols and platforms’, the Sm14
project was initiated by gathering observations from animal models of infection together with logical
progression based on experimental evidence.
The first original approach was in the methodology for generating a worm extract that was
subsequently used to assess protective immunity. Rather than lyophilized parasites, generally used by
other research groups, a saline extract containing secreted/excreted antigens derived from living adult
schistosomes was utilized for initial immunizations. The restricted number of potential protective
antigens released in this saline extract allowed an accelerated identification of strong antigen candidates
for molecular analysis and gene cloning [18–22]. Innovative methods were also adopted for the
assessment of immunity, where the use of outbred models, in contrast to the commonly-employed
inbred animals, allowed a better representation of the ultimate target population and provided a
unique opportunity to develop an alternative strategy for the assessment of protective immunity.
The analyses were stratified based on the measurement of frequencies of worm burdens within
vaccinated animal populations as compared with non-vaccinated infected controls, as opposed to
evaluation of mean values of parasite loads, as usually adopted. A solid base of pre-clinical data was
generated establishing the immunization protocols that would be adopted during the following steps
of the development [23–31].
As molecular biology tools evolved and gene-cloning techniques became available, several
antigens released in the saline culture medium of live schistosomes, were cloned and sequenced.
Serum from rabbits immunized with the ‘saline extract’ was used to screen an adult S. mansoni
cDNA library and the most promising antigen was identified as a member of the fatty acid binding
protein (FABP) family, termed Sm14 [32]. Molecular modeling studies from our group predicted the
beta-barrel structure of the Sm14 [33] that was later experimentally confirmed by crystallography [34]
and nuclear magnetic resonance [35]. These analyses allowed the engineering of a stabilizing mutation
that conferred a remarkable long-term stability, while maintaining the function and immunogenicity
of the antigen [36].
Sm14 was shown to be particularly important to helminths, which are not capable of synthetizing
fatty acids but rely on these being provided by the host species. Lipids, apart from being constituents
of membranes, have important roles in development of different lifecycle stages and the evasion of
immune responses both by adult worms and larvae [37]. In addition to the publication describing the
a FABP family member in Schistosoma mansoni [32], different groups published the identification of
homologous FABP protein members from FABP family in many helminths of human and veterinary
importance. Of particular importance was the identification of the F. hepatica FABP [38]. F. hepatica is
the main parasite of livestock worldwide. We have managed to successfully test Sm14 vaccination
against F. hepatica in mice, followed by two independent experiments in sheep, one of the definitive
host species for fascioliasis [39]. These experiments that demonstrated that Sm14 is also protective
against F. hepatica infection has led to Sm14 being developed in parallel as the molecular basis for
a veterinary vaccine by FIOCRUZ, in collaboration with the private Brazilian company Ourofino
Animal Health.
Trop. Med. Infect. Dis. 2018, 3, 121 6 of 10

3. Clinical Studies
The licensing of the Sm14 patents for veterinary use gave birth to a public–private partnership
(PPP) model of product development that rendered significant visibility to the Sm14 vaccine project.
Such a gain in momentum was followed by strong support for human vaccine development by the
Brazilian government project financing agency (FINEP) that allowed the use of contract research
organizations (CROs) for antigen production, quality control and fill-finish in world-class academic
GMP facilities based in the United States of America in collaboration with the Ludwig Institute for
Cancer Research, Cornell University and the Infectious Disease Research Institute (IDRI, Seattle, USA).
In order to have a consistent, stable and defined final product for clinical human use, the Sm14
antigen was formulated with the synthetic adjuvant glucopyranosyl lipid A (GLA-SE), an adjuvant
successfully tested in clinical trials with different human vaccine candidates.
In December of 2010, the Brazilian Health Regulatory Agency (ANVISA) approved a phase Ia
clinical trial in 20 healthy male volunteers from a non-endemic area (Rio de Janeiro, Brazil) to evaluate
the safety of the investigational product. The study was conducted by the Brazilian National Institute
of Infectious Diseases (INI/FIOCRUZ). The results of this first trial demonstrated the safety of the
vaccine in the studied population, showing no systemic reactogenicity. No serious adverse events
were associated to the investigational product [15]. A phase Ib clinical study, to evaluate the safety and
immunogenicity of the vaccine preparation in 10 healthy women volunteers, was also then successfully
concluded in 2012 (manuscript in preparation).
In 2015–2016, within the scope of a CEWG Demonstration Project, a phase IIa trial was developed
in 30 male adults living in a highly endemic area for both S. mansoni and S. haematobium in the Senegal
River Basin. The trial was conducted by a specialized team from Espoir Pour La Santé (EPLS), linked
to the Pasteur Institute of Lille (IPL, France), headed by Dr. Gilles Riveau (IPL) in conjunction with the
FIOCRUZ group and the Brazilian biotechnology company Orygen Biotecnologia the license holder
of Sm14 for human use (ClinicalTrials.gov Identifier: NCT03041766) [40]. The main objectives of
the trial were safety and immunogenicity of the Sm14/GLA-SE vaccine. These objectives were fully
achieved. The investigational product rSm14 (50 µg) formulated with GLA-SE in two dosages (2.5 µg
and 5 µg/dose, denominated groups 1 and 2, respectively) and administered intramuscular (IM),
was shown to be safe with no observed serious adverse events in either group. The most common
reactions were local pain and heaviness of the vaccinated arm. These reactions were transitory and
mild. Seroconversion of 92% of individuals after the second dose were observed, similar to the
pattern observed in the phase I trials [15]. Immunogenicity based on additional cellular responses,
memory cells and T cell activation markers were analyzed at IDRI in an extensive panel focusing on
the identification of a vaccine-related immune response.
After the completion of the phase IIa trial and based on the observed induction of a strong and
long-lasting immune response, an extension study to assess the possible persistence and profile of
this response beyond the initial schedule of the trial was duly authorized by Senegalese Ministry of
Health (MoH). This was carried out between August and December 2017 with the inclusion of two
additional time points, 9 and 12 months, after the first vaccine injection. ELISA tests performed at
Centre de Recherche Biomédicale/Espoir Pour La Santé (EPLS) showed the persistence of significant
specific antibody titers up to 12 months after the first vaccination dose with Sm14/GLA-SE (manuscript
in preparation).
A phase IIb trial design and protocol were defined in January 2018, based on the results of the
phase IIa trial in adults. The phase IIb trial will involve 95 school children from 7–11 years of age living
in the same endemic area for both S. mansoni and S. hamatobium of the Senegal River Basin region.
Ethical committee approval and regulatory approval from the Senegalese MoH have been obtained.
EPLS has already initiated the trial in the same region as the original phase IIa trial in adults, using
the same lot of GMP Sm14 under a regimen of three IM doses of 50 µg/dose formulated with 2.5 µg
of GLA-SE, 30 days apart. The phase IIa and b trials are largely funded by Orygen Biotecnologia in
conjunction with FIOCRUZ and with support of CEWG-WHO platform and financial fund.
Trop. Med. Infect. Dis. 2018, 3, 121 7 of 10

4. Sm14 +GLA-SE: A Humanitarian Anti-Schistosomiasis Vaccine

During the process of analysis by WHO member state representatives, within a regional structure,
and extensive subsequent analysis by technical experts and ad hoc committees, the Sm14 schistosomiasis
vaccine, was selected by the WHO Executive Board as one of the current list of six demonstration projects.
A stakeholders meeting organized by WHO at its Geneva headquarters was held in June 2015 prior to
the release of the first installment of funding. During the process of selection and shortlisting of the
candidate demonstration projects presented projects, discussions on the scientific merits, state of the art
of the project and requirement for full adherence to CEWG principles, much was learned concerning the
mandatory need to assure the accessibility and affordability of this vaccine to the poor endemic countries
in which it will ultimately be used [14].
From its inception, the Sm14 schistosomiasis vaccine has been designed to be both effective and
low-cost. To achieve this goal, several innovations for vaccine development were implemented and
a strong effort was made to choose intellectual property-free components [36]. This has led to the
successful development of a very low-cost, stable product involving a large-scale production process.
De-linkage of final product price from the costs of the long R&D phases has been achieved by
Sm14 being initially developed at a governmental scientific foundation (FIOCRUZ) with support from
funds from public Brazilian financial institutions (FINEP and FAPERJ).
After 2005, licensing of FIOCRUZ patent rights for human use to a private Brazilian company
was through contracts designed to protect the accessibility, affordability and supply strategies for the
lower- and middle-income countries (LMIC) that are the target areas to receive the anti-schistosomiasis
vaccine. The presently licensee company, Orygen Biotecnologia, is a startup company wholly owned
by two of the largest Brazilian pharmaceutical companies. Its involvement in the final development of
the Sm14 human vaccine is crucial. The company has agreed to a cost plus pricing strategy, as adopted
by WHO for vaccine pricing [41].
In parallel, the veterinary anti-fasciola vaccine is being developed in keeping with current
European guidelines to reduce the presence of anti-helminthic drug chemical residues in milk and
meat of livestock. It is aimed at rich countries and markets and designed to contribute/support future
potential large-scale delivery programs.
We are no longer at a stage when an anti-schistosomiasis vaccine is to be discussed, attacked
or delayed, as it was for decades along with all anti-parasite vaccines. Our knowledge concerning
vaccines has improved enormously, as have the technical resources available. Vaccines represent the
intervention strategy with the best cost–benefit ratio thus far applied in public health. Moreover,
transmission control of infectious/transmissible diseases has only been achieved through vaccination.
Sanitation, chemotherapy and health education are not sufficient to eliminate parasitic diseases that
disproportionally affect people living in poor countries. Immunization with a safe and effective
vaccine can contribute to a long-term reduction of schistosome egg excretion from the host, thus truly
controlling transmission. So far, there are no vaccines against the parasites that afflict countries fighting
to emerge from poverty and reach better conditions of health and overall development.
The Sm14 vaccine against schistosomiasis is being developed as a humanitarian vaccine to
be included in effective schistosomiasis transmission control programs that will hopefully invert
the paradigm for a north-to-south route for technology generation and contribute to the broad
use of the most safe, effective and environmentally and human-friendly health-promoting strategy,
prophylactic vaccination.

Funding: This study was funded by FINEP (Financiadora de Estudos e Projetos), grant number 01.06.105800;
FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro), grant number
E-26/010.001533/2014; IOC/FIOCRUZ (Instituto Oswaldo Cruz/Fundação Oswaldo Cruz, Ministério da Saúde)
and Orygen Biotecnologia S.A.is supporting phase II/III clinical trials, process development for large scale
production and steps forward to final product.
Trop. Med. Infect. Dis. 2018, 3, 121 8 of 10

Acknowledgments: The authors would like to thank Steven Reed, Rhea Coler, Tracey Day, Anna Marie Beckman
and IDRI team for immunogenicity tests and stability tests on Sm14 GMP lot; Orygen Biotechnologia technical
team; Marcia Ciol, statistician from WA University; Gilles Riveau and Anne-Marie Schacht from EPLS/IPL;
Tatiane dos Santos, FIOCRUZ—Instituto Oswaldo Cruz, Laboratório de Esquistossomose Experimental, for part
of immunology tests.
Conflicts of Interest: The authors declare no conflict of interest.

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